Module 2.

1a Reading Materials

A Chinese Medicine Approach in Treating Depression by Promoting Liver Qi

Circulation: A Modern Medicine Perspective

Summary

Depression is a mental illness that is particularly prevalent in developed countries. In

Modern Medicine, experimental and clinical investigations have demonstrated that
depression is associated with the dysregulation of neurotransmitter signaling, and
symptoms of depression can be alleviated by therapeutic interventions targeted at
this level. However, patients taking antidepressant drugs often experience serious
side effects and high relapse rates. On the other hand, Chinese Medicine views
depression as a manifestation of Liver Qi stagnation (肝氣鬱結). Practitioners
of Chinese Medicine have long treated depression with herbs that promote Qi
circulation in the liver. In this article, we offer a hypothesis involving the biochemical
basis of a linkage between Liver Qi stagnation and depression. Liver Qi is involved in
the processing of macronutrients into molecules to fuel energy metabolism in brain
neurons, as well as the synthesis of plasma proteins that maintain blood circulation
to the brain, thereby enabling these fuel molecules to be delivered to the brain.
In cases of Liver Qi stagnation, the failure in delivering sufficient fuel molecules
to the brain disrupts mitochondrial ATP production in neurons. Because
neurotransmitter release and neurotropin transport are driven by ATP, the
deficiency in release and/or transport processes resulting from insufficient ATP
production could lead to depression. Therefore, if Liver Qi stagnation is causally
related to the pathogenesis of depression, the promotion of Liver Qi circulation
by Chinese herbs might offer a promising prospect for the effective treatment of
depression.

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Depression is a common disorder affecting over 350 million people worldwide,
particularly in industrialized countries, making it a leading cause of disability. In Hong
Kong, the yearly prevalence of major depressive disorders is 8.4%. Depressed patients
exhibit a wide range of affective, cognitive, behavioral and physiological symptoms.
They experience sadness, anxiety, feelings of worthlessness and guilt; they engage in
self-denigration and rumination; they experience anhedonia, tearfulness, psychological
retardation and undefined pain; they stop practicing personal hygiene and they exhibit
changes in appetite, sleep, and libido. In the worst-case scenario, depression can even
lead to suicide.

Pathogenesis of Depression a Modern Medicine Perspective

Modern Medicine describes the etiology of depression in terms of biological,

psychological, social and socio-cultural factors. Biologists have attributed depressive
symptoms to genetic factors, disturbances in circadian rhythm, high cortisol levels,
defective negative feedback in the hypothalamic-pituitary-adrenal (HPA) axis, and
abnormalities in neurotransmission and brain structure. Specifically, it is believed that
deficient serotonergic signaling has pathological implications in depression.

Chronic stress-induced neuro-inflammation and abnormalities in neurotransmission can

contribute to depression. After a chemical signal is transduced, the actions of
neurotransmitter molecules are terminated by neuronal reuptake and/or degradation.
Increased neurotransmitter degradation and/or reuptake can result in excessively low
levels of serotonin, norepinephrine and dopamine in synaptic clefts, resulting in
defective transmission of neural signals. It is worth noting here that pro-inflammatory
cytokines have also been shown to promote reuptake of serotonin through activation of
its transporters, thereby decreasing the concentration of serotonin at the synapse where
it functions as a neurotransmitter.

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Altered neurotransmission has been postulated to be the biochemical basis for
antidepressant drug action in Modern Medicine. As their names suggest, selective
serotonin reuptake inhibitors (SSRIs) and serotonin-norepinephrine reuptake inhibitors
(SNRIs) block the reuptake of these neurotransmitters into presynaptic neurons.
Monoamine oxidase inhibitors (MAOIs) decrease neurotransmitter degradation following
their reuptake into presynaptic terminals.

While antidepressant medications in Modern Medicine have been proven to be clinically

effective, their use has been limited by potentially serious side effects. For example,
MAOIs interact with certain foods or medications, causing high fever, disseminated
intravascular coagulation, muscle rigidity, convulsions, and even coma. Increased
suicidal ideation is another possible side effect of antidepressant medications. Moreover,
currently used antidepressants provide only temporary relief of symptoms but are not
curative. Symptoms of depression can return if patients discontinue their medication.
Therefore, it is of great therapeutic interest to explore alternative treatments with fewer
side effects and improved therapeutic efficacy.

Chinese Medicine is a time-honored practice in China and many Asian countries. While
Modern Medicine adopts a reductionist approach to elucidating the biochemical basis of
diseases, Chinese Medicine views body functions holistically on the basis of more
abstract theories. A practitioner of Chinese Medicine treats illness by first identifying the
underlying cause or “syndrome”. In this regard, Chinese Medicine treatment can be
curative rather than merely symptom-relieving. Furthermore, Chinese Medicine makes
use of multiple ingredients in herbal prescriptions to synergize therapeutic actions while
minimizing toxicity to the body. In this way, the characteristic features of Chinese
Medicine may confer advantages over the Modern Medicine approach to treating
depression.

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Pathogenesis of Depression - a Chinese Medicine Perspective

Depression is called yi-yu-zheng (憂鬱症) in Chinese. Transliterally, yi-yu denotes a

“clogged” or “stagnant” status of Qi. In Chinese Medicine, yu describes a collection
of syndromes that are characterized by the obstruction of Qi circulation. Many
disorders - including depression - are attributable to Qi stagnation, the treatment of
which involves the use of herbs that promote Qi decongestion. Generally referred
to as “vital energy” in the Western world, Qi can be viewed as the functional
manifestation of organ viability in the body. Qi can also be regarded as a substance
partially derived from dietary nutrients, which nourishes every organ in the body. The
effects of Qi can be manifested in visible forms such as blood, mucous and serous
fluids. In addition, Qi can favor the conversion of food into fuel molecules, which then
undergo oxidative phosphorylation to generate ATP. In this regard, ATP can be
viewed as the biochemical unit of Qi in the cell from a modern medicine perspective.
While Qi cannot be measured directly, problems related to Qi can manifest as
physiological disorders.

The liver plays a pivotal role in Qi circulation. Through regulating the flow and activity
of Qi, the Liver promotes optimal circulation of blood as well as digestion and
metabolism in the spleen and stomach. Liver synthesizes plasma proteins, such as
albumin, which maintain the osmotic pressure of the blood. Without these proteins,
water would leave blood vessels by osmosis, causing edema in tissues and
hypovolemia in the blood. Furthermore, the liver metabolizes carbohydrates,
lipids, and amino acids for dissemination through the circulatory system.
Hence, the proper flow and function of Liver Qi is crucial to one’s health. Indeed,
the importance of Liver Qi is reflected in the practice of Chinese Medicine which
uses various means for “soothing the liver” to relieve stress and anxiety.

Two factors can contribute to the aggravation of liver Qi stagnation: phlegm and
anger. Qi can influence with the physical properties of blood, mucous fluid and serous
fluid, all of which are its functional manifestation. When Qi becomes clogged, other
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lose the driving force which allows them to flow smoothly. Dampness then accumulates
and eventually gives rise to phlegm, which is sticky and can further inhibit the flow of Qi.
If phlegm invades body regions above the chest, this can result in mental confusion. On
the other hand, the “seven emotions” in Chinese Medicine, namely, joy, anger, anxiety,
grief, fear, shock, and melancholy, are also related to the functioning of specific organs.
Anger can impair liver function, and when it acts in concert with stress, the optimal
circulation of liver Qi will be impaired.

According to the Five Element theory, Wood (the liver) generates Fire (the heart or
brain), which implies a supportive role of Liver in brain function. Liver Qi stagnation can
therefore manifest itself as the malfunctioning of the central nervous system. For
instance, the obstruction of bile flow causes an increase in bilirubin concentration in the
liver and then in the blood, resulting in jaundice with yellow pigmentation visible in the
eyes. Furthermore, the increased amount of bilirubin can enter the brain through a leaky
blood-brain barrier, where it is differentially accumulated in the hippocampus and basal
ganglia, with resultant neurotoxicity. As newborn babies have an underdeveloped (and
hence highly permeable) blood-brain barrier, they are especially vulnerable to this type
of neurotoxicity which referred to as kernicterus.

Given the current understanding of depression from both Modern Medicine and Chinese
Medicine perspectives, one can hypothesize that the blockage in Liver Qi can influence
the endocrine and central nervous systems, resulting in depression.

Pathological linkage between Liver Qi Stagnation and Depression

Chinese Medicine views the liver as a crucial organ in the regulation of Qi. Firstly, the
liver promotes the generation of Qi, wherein it metabolizes carbohydrates, lipids, and
amino acids from foodstuffs producing fuel molecules. Secondly, the liver promotes the
dissemination of these fuel molecules through the blood by synthesizing plasma
proteins that maintain blood volume and thus a proper blood flow. Individual cells can

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then take up the fuel molecules and convert them into ATP through oxidative
metabolism. In the cell, ATP acts as the biochemical unit of Qi, which is universally
required for cellular activities.

ATP plays a particularly important role in the functioning of the nervous system. Indeed,
ATP hydrolysis is a crucial step in the accumulation of neurotransmitters inside synaptic
vesicles. Hence, ATP (ie., biochemical unit of Qi) is consumed to drive the process of
neurotransmission. Furthermore, ATP facilitates the release of neurotransmitters into
the synaptic cleft.

In addition, ATP is indispensable in the trafficking of growth signals. Neurotrophins first

enter the target neuron at the axon terminal through receptor-mediated endocytosis.
They subsequently undergo retrograde transport to the nucleus and activate genes that
promote cell growth and survival. The process of retrograde transport requires the
motor protein dynein, which carries the endosome vesicle along the microtubule. ATP is
reuqired produce conformational changes in dynein, which enables it to be transported
along the length of the neuron. Therefore, dynein consumes ATP to energize the
transport of growth factors in the neuron. Without a sufficient supply of ATP, neurons do
not receive adequate growth signals and neuro-degeneration occurs, leading to
defective neurotransmission.

Conclusion

Recent studies in Modern Medicine have shown that depression is likely caused by the
dysregulation of neurotransmission- which, according to Chinese Medicine theory, is a
consequence of Liver Qi stagnation. It is suggested that the experience of anger and/or
stress disrupts Qi circulation in the liver, leading to a deficiency in fuel molecule
production and plasma protein synthesis. Thus, the hippocampus and prefrontal cortex
are not sufficiently nourished by Qi, leading to defective neurotransmitter signaling
resulting in depression. Based on this understanding, the etiology of depression in
terms of Chinese Medicine theory becomes self-explanatory, and it serves as a
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rationale for the treatment of depression using herbal formulations which produce a
holistic treatment.

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A schematic diagram of liver Qi circulation between the liver and the brain under
normal physiological conditions and depression